Investigational New Drugs最新文献

HP518 is an oral PROteolysis TArgeting Chimera (PROTAC) protein degrader targeting the wild-type androgen receptor (WT-AR) and mutant AR ligand-binding domain (AR-LBD). A multicenter, first-in-human, open-label Phase 1 dose escalation study was conducted in patients with metastatic castration-resistant prostate cancer (mCRPC) to evaluate the safety, pharmacokinetics, and anti-tumor activity of HP518. Twenty-two patients with mCRPC with disease progression on at least 1 novel androgen receptor pathway inhibitor (ARPI) and ≤ 1 line of chemotherapy received HP518 once daily orally in sequential cohorts. Patients were not selected for AR-LBD mutations. Objectives were to assess safety, tolerability, maximum tolerated dose, pharmacokinetics (PK), as well as efficacy by PSA₅₀ response and radiographic response per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and Prostate Cancer Working Group 3 (PCWG3) criteria. Exploratory objectives included genomic profiling using cell-free DNA. The majority of treatment-emergent adverse events (TEAEs) were Grade 1 or 2. The most common AEs were nausea and vomiting, fatigue, constipation, diarrhea, and decreased appetite. Only one (vomiting) out of 10 serious adverse events (SAE) was considered drug-related. No patient experienced a dose-limiting toxicity (DLT), and no AEs led to dose reduction or study discontinuation. Following multiple dosing of HP518, the PK appeared to plateau showing a less than dose-proportional relationship between exposure and dosage. Two patients demonstrated a partial response, and three patients showed a PSA50 response. In this initial Phase 1 study, HP518 demonstrated an acceptable safety profile and responses in a limited subset of mCRPC patients with progression after ARPI warranting further investigation. ClinicalTrials.gov Identifier: NCT05252364.

RMX1002 (grapiprant) is a selective E-type prostanoid receptor 4 (EP4) antagonist and a promising candidate for cancer therapy, potentially enhancing anti-tumor immune responses. This study aimed to evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of RMX1002 as monotherapy and in combination with anti-PD-1 antibody toripalimab for advanced solid tumors. This multicenter, phase I trial enrolled patients with histologically or cytologically confirmed advanced solid tumors. This study included three phases: Ia (dose-escalation of RMX1002 monotherapy from 200 to 650 mg BID), Ib (dose-escalation from 500 to 650 mg BID in combination with toripalimab), and Ic (dose-expansion of 500 mg BID with toripalimab). Safety, pharmacokinetics, pharmacodynamics, and efficacy were assessed. A total of 45 patients were enrolled (17 in phase Ia, 12 in phase Ib, and 16 in phase Ic). No dose-limiting toxicity was reported, and the MTD was not reached. Overall, 21 patients experienced RMX1002-related adverse events with CTCAE grade ≥ 3. Pharmacokinetics revealed rapid absorption of RMX1002 with the maximum concentration (C_max) reached within 2 to 5 h, and dose-dependent increases in C_max and area under the concentration-time curve. The increase in urinary metabolite of PGE2 suggested the inhibition of EP4 signaling pathway. The best response was stable disease, reported in 64.7%, 28.6%, and 18.8% of patients in phase Ia, Ib, and Ic, respectively. RMX1002 was well tolerated and showed a best response of stable disease. RMX1002 500 mg BID with toripalimab 240 mg every 3 weeks is the recommended dose for future trials.

The US (US) Food and Drug Administration (FDA)-accelerated approval pathway facilitates early access to oncology drugs based on surrogate endpoints, with required confirmatory post-marketing trials. However, regulatory decisions vary globally, with some drugs withdrawn in the US remaining approved in Japan. We conducted a cross-sectional analysis of Japanese professional society guidelines, evaluating recommendations for seven accelerated approval cancer drugs withdrawn from the US market but retained in Japan. We assessed for level of evidence and level of treatment preference ratings with consensus across guidelines issued by the corresponding Japanese professional societies. Four of the seven drugs (57%) were recommended as highly or moderately preferred treatment options in Japanese guidelines: gemtuzumab ozogamicin for acute myeloid leukemia, gefitinib for EGFR-positive non-small cell lung cancer, bevacizumab for HER2-negative metastatic breast cancer, and atezolizumab with nab-paclitaxel for PD-L1-positive triple-negative breast cancer. Detailed analysis of regulatory history and background of guideline recommendation revealed discrepancies in the assessment of clinical benefits: gemtuzumab ozogamicin failed to demonstrate benefits amid safety concerns, while gefitinib, bevacizumab, and atezolizumab were more controversial, although they did not demonstrate improved overall survival in post-marketing trials. Despite regulatory withdrawal in the US due to unproven clinical benefits, drugs retained in Japan received positive guideline recommendations. This finding highlights regional variations in regulatory decisions and different approaches to benefit-risk assessments, suggesting a need for improved transparency in Japan's regulatory decisions and guideline recommendations, with clearer justifications for endorsing drugs that are considered to have unproven clinical benefits in the US.

Cancer immunotherapy has revolutionized tumor treatment. However, robust and effective testing platforms remain lacking, especially for the selection of the optimized therapy at the patient-specific level. Unlike conventional treatment evaluations, testing platforms for cancer immunotherapy must incorporate not only tumor cells but also the tumor microenvironment (TME), including immune components. Recently, emergence of patient-derived tumor organoids (PDTOs), an in vitro preclinical model, has provided a novel approach for studying tumor evolution and assessing treatment responses, and shows great potential when coculturing with immune cells to study the mechanisms of immunotherapy efficacy and resistance. However, traditional organoid technology is limited in capturing the full impact of the TME on tumor behaviors due to the absence of stromal components. To circumvent these restrictions, complex organoid cocultures with immune cells, cancer-associated fibroblasts and vasculatures are developed. In this review, we summarized recent advances in PDTO culture techniques for modeling the TME and explored the application of complex tumor organoids in cancer immunotherapy.

T cells are crucial regulators in cancer treatment due to their cytotoxic ability. Recently, immunotherapies based on bispecific antibodies (Bi-Ab) have achieved remarkable effects in cancer treatment, attributed to their capability of recruiting and activating T cells to kill tumors. In the present study, we investigated whether CD155 is an effective target for T-cell-mediated immunotherapy against human gynecological malignancies. We demonstrated that CD155 is expressed on common gynecological tumor cells, including cervical, uterine, and ovarian cancers. Next, we evaluated the specific cytotoxic activity of T cells armed with CD155Bi-Ab (CD155Bi-T cells) against tumor cells. Compared with control T cells treated with separate anti-CD155 and anti-CD3 mAbs, CD155Bi-T cells exhibited significant cytotoxicity against CD155-positive gynecological tumor cells. Specifically, in the luciferase assay, the cytotoxicity of CD155Bi-T cells was 2.67-fold higher than that of control T cells at an effector/target ratio of 5:1, indicating a significant enhancement in tumor-killing activity. This enhanced cytotoxic activity was further supported by increased expression of activation markers (CD69 and 4 - 1BB), higher production of T-cell-derived cytokines (IL- 2, IFN-γ, and TNF-α), and elevated levels of the cell-killing mediators (perforin and granzyme B). Taken together, our findings demonstrate that CD155 is a promising target for gynecological tumors, and CD155Bi-T cells hold significant potential for immunotherapy against CD155⁺ gynecological malignancies.

Immune encephalitis (IE) is an immune-mediated adverse events (irAEs) linked to nivolumab therapy, and its clinical characteristics remain unclear. This study aimed to analyze the clinical patterns of nivolumab-induced IE to inform diagnosis, treatment, and prevention strategies. We conducted a retrospective analysis of nivolumab-induced IE by reviewing case reports from the database until October 31, 2024. Among the 86 patients (53.5% male), the median age was 64 years (range 17, 83). The median time to the onset of IE was 38 days (range 4, 1430), and the median treatment cycle was 2 cycles (range 1, 18). The most prevalent symptoms included altered mental status (38.4%) and fever (37.2%). Cerebrospinal fluid analysis revealed elevated protein levels, normal glucose, and pleocytosis. Antineuronal antibodies were present in 29.1% of patients. MRI findings typically showed T2/FLAIR hyperintense signals in 52.3%. EEG results indicated diffuse slowing (16.3%). Following drug discontinuation and treatment, 86% of patients exhibited recovery or improvement, while 5.8% unfortunately succumbed to the condition. IE represents a rare yet severe irAEs associated with nivolumab. Clinicians must remain vigilant for signs of IE in patients undergoing nivolumab treatment. Diagnostic tests for nivolumab-induced IE generally do not reveal specific abnormalities. For individuals diagnosed with IE, it is crucial to initiate systemic steroid treatment without delay.

Pembrolizumab has shown links to autoimmune encephalitis (AE), yet the exact clinical characteristics remain unclear. This study examines the clinical features of pembrolizumab-induced AE to enhance diagnostic accuracy and therapeutic strategies. Reports on pembrolizumab-induced AE were gathered via a searchable database, culminating on November 30, 2024. The median age at onset among the 34 patients was 68 years (range 47-82), with males constituting 67.6%. The average onset period for AE was 6 months (range 0.3-25) after the initial dose, with an average of 6 cycles (range 1-17). Commonly reported symptoms included confusion (38.2%), fever (35.3%), and decreased consciousness (32.4%). Cerebrospinal fluid analysis revealed elevated protein (55.9%), leukocytosis (70.6%), and normal blood glucose levels (38.2%). Antineuronal antibodies were found to be negative in 41.2% of cases and positive in 35.3%. Magnetic resonance imaging indicated T2/FLAIR hypersignal in 32.4% of cases, while the electroencephalogram revealed slow waves (11.8%) and diffuse slowing (11.8%). Following treatment with steroids, intravenous immunoglobulin, and plasmapheresis, 82.4% of patients experienced symptom improvement or recovery, though 5.9% succumbed to AE. Oncologists must consider the risk of AE when prescribing pembrolizumab. Early diagnosis and intervention for AE are crucial. Further research is needed to define the optimal treatment approach.

Multiple myeloma (MM) is a prevalent bone marrow cancer that often presents challenges due to treatment resistance. This study assessed the apoptotic and antiproliferative effects of the Polo-like kinase 1 inhibitor MLN0905, alone and in combination with lenalidomide, in an MM cell line. The AMO1 human MM cell line was treated with various doses of lenalidomide, MLN0905, or their combination. Cell viability was assessed via the MTT assay, and apoptosis was quantified via Annexin V/propidium iodide staining. The effects of treatment on BCL2, p21, and PUMA gene expression were evaluated through quantitative real-time polymerase chain reaction. The IC50 values were 50.61 μM for lenalidomide and 54.27 nM for MLN0905, indicating dose-dependent cytotoxic effects. When 30 μM lenalidomide was combined with 50 nM MLN0905, the percentage of apoptotic cells increased to 51.31%. The SynergyFinder platform identified optimal synergy at 40 μM lenalidomide plus 50 nM MLN0905. MLN0905 significantly reduced p21, PUMA, and BCL2 mRNA levels, whereas lenalidomide increased p21 and PUMA mRNA expression and decreased BCL2 expression. The combination treatment notably increased p21 expression and significantly reduced BCL2 levels, with no marked change in PUMA mRNA. This study revealed that MLN0905 significantly affects AMO1 cell survival, reducing the mRNA expression of genes involved in apoptosis and the cell cycle in a dose-dependent manner. Furthermore, the combination of lenalidomide and MLN0905 synergistically decreases cell survival and induces apoptosis in AMO1 cells. The altered expression of apoptotic genes highlights the potential of this drug combination for future multiple myeloma research.

Background: Immune checkpoint inhibitors (ICIs) combined with anti-vascular endothelial growth factor (VEGF) have been the standard first-line treatment of hepatocellular carcinoma (HCC). However, the efficacy of this combination in post-line treatment is still unknown. This study aimed to evaluate the efficacy and safety of the combination of anti-PD-L1 envafolimab and novel humanized anti-VEGF suvemcitug as second-line treatment for patients with HCC.

Methods: This open-label, prospective phase II clinical study (NCT05148195) comprised safety run-in stage and dose expansion stage of HCC cohort. Eligible patients were aged ≥ 18 years and had undergone at least a prior line of treatment. Patients received fixed-dose envafolimab and suvemcitug until termination of disease progression, unacceptable toxicities, or withdrawal. The primary endpoint of safety run-in stage was recommended dose (RD), and dose expansion stage was objective response rate (ORR).

Results: As of August 10, 2023, no dose-limiting toxicity was observed in six patients in the safety-run-in stage, and 2 mg/kg dose every 3 weeks was declared the RD of suvemcitug. Among 20 patients with HCC, the median age was 54.5 (range, 42-70) years. Of these patients, 20 (100.0%) received ≥ one prior line treatment, with 20 (100%) received tyrosine kinase inhibitor (TKI) treatment and 8 (40.0%) received prior ICI treatment. The ORR was 10.0% (95% confidence interval (CI), 1.2-31.7), DCR was 65.0% (95% CI, 40.8-84.6), and DoR was not reached (NR). With a median follow-up of 13.9 months, the median progression-free survival (PFS) and median overall survival (OS) were 4.3 months (95% CI, 1.4-8.1) and 10.7 months (95% CI, 6.0-not evaluable [NE]), respectively. Treatment-related adverse events (TRAEs) of grade ≥ 3 occurred in 40% patients, with proteinuria (20.0%, 4/20) being the most frequent. The ORR of no lung metastasis, prior first-line treatment and IO naïve treatment subgroup was 16.7%.

Conclusions: The combination of envafolimab and suvemcitug showed a tolerable safety profile and promising antitumor activity in HCC patients who failed later-line treatment.